DESCRIPTION

Naratriptan tablets contain naratriptan as the hydrochloride,
which is a selective 5-hydroxytryptamine1 receptor
subtype agonist. Naratriptan hydrochloride is chemically designated as
N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethanesulfonamide
monohydrochloride, and it has the following structure:

CLINICAL PHARMACOLOGY

Mechanism of Action

Naratriptan binds with high affinity to 5-HT1D and 5-HT1B receptors and has no significant affinity
or pharmacological activity at 5-HT2-4 receptor subtypes
or at adrenergic α1, α2, or β;
dopaminergic D1 or D2; muscarinic; or benzodiazepine
receptors.

The therapeutic activity of
naratriptan in migraine is generally attributed to its agonist activity
at 5-HT1D/1B receptors. Two current theories have been
proposed to explain the efficacy of 5-HT1D/1B receptor
agonists in migraine. One theory suggests that activation of 5-HT1D/1B receptors located on intracranial blood vessels, including
those on the arteriovenous anastomoses, leads to vasoconstriction,
which is correlated with the relief of migraine headache. The other
hypothesis suggests that activation of 5-HT1D/1B receptors
on sensory nerve endings in the trigeminal system results in the inhibition
of pro-inflammatory neuropeptide release.

In
the anesthetized dog, naratriptan has been shown to reduce the carotid
arterial blood flow with little or no effect on arterial blood pressure
or total peripheral resistance. While the effect on blood flow was
selective for the carotid arterial bed, increases in vascular resistance
of up to 30% were seen in the coronary arterial bed. Naratriptan has
also been shown to inhibit trigeminal nerve activity in rat and cat.
In 10 human subjects with suspected coronary artery disease (CAD)
undergoing coronary artery catheterization, there was a 1% to 10%
reduction in coronary artery diameter following subcutaneous injection
of 1.5 mg of naratriptan.

Pharmacokinetics

Naratriptan tablets are well absorbed, with about
70% oral bioavailability. Following administration of a 2.5 mg tablet
orally, the peak concentrations are obtained in 2 to 3 hours.
After administration of 1 or 2.5 mg tablets, the Cmax is
somewhat (about 50%) higher in women (not corrected for milligram-per-kilogram
dose) than in men. During a migraine attack, absorption was slower,
with a Tmax of 3 to 4 hours. Food does not affect
the pharmacokinetics of naratriptan. Naratriptan displays linear kinetics
over the therapeutic dose range.

The steady-state
volume of distribution of naratriptan is 170 L. Plasma protein
binding is 28% to 31% over the concentration range of 50 to 1,000 ng/mL.

Naratriptan is predominantly eliminated in urine,
with 50% of the dose recovered unchanged and 30% as metabolites in
urine. In vitro, naratriptan is metabolized by a wide range of cytochrome
P450 isoenzymes into a number of inactive metabolites.

Special Populations

Age

Race

The effect of race on the pharmacokinetics of naratriptan
has not been examined.

Renal Impairment

Clearance of naratriptan was reduced by 50% in patients
with moderate renal impairment (creatinine clearance, 18 to 39 mL/min)
compared to the normal group. Decrease in clearances resulted in an
increase of mean half-life from 6 hours (healthy) to 11 hours
(range, 7 to 20 hours). The mean Cmax increased by
approximately 40%. The effects of severe renal impairment (creatinine
clearance, ≤15 mL/min) on the pharmacokinetics of naratriptan
has not been assessed (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).

Hepatic Impairment

Clearance of naratriptan was decreased by 30% in
patients with moderate hepatic impairment (Child-Pugh grade A or B).
This resulted in an approximately 40% increase in the half-life (range,
8 to 16 hours). The effects of severe hepatic impairment (Child-Pugh
grade C) on the pharmacokinetics of naratriptan have not been assessed
(see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).

Drug Interactions

In normal volunteers, coadministration of single
doses of naratriptan tablets and alcohol did not result in substantial
modification of naratriptan pharmacokinetic parameters.

From population pharmacokinetic analyses, coadministration
of naratriptan and fluoxetine, beta-blockers, or tricyclic antidepressants
did not affect the clearance of naratriptan.

Naratriptan does not inhibit monoamine oxidase (MAO) enzymes
and is a poor inhibitor of P450; metabolic interactions between naratriptan
and drugs metabolized by P450 or MAO are therefore unlikely.

Oral Contraceptives

Oral contraceptives reduced clearance by 32% and
volume of distribution by 22%, resulting in slightly higher concentrations
of naratriptan. Hormone replacement therapy had no effect on pharmacokinetics
in older female patients.

Smoking increased
the clearance of naratriptan by 30%.

CLINICAL TRIALS

The efficacy of naratriptan tablets in the acute treatment
of migraine headaches was evaluated in 6 randomized, double-blind,
placebo-controlled studies of which 4 used the recommended dosing
regimen and were conducted as outpatient trials. Three of these studies
enrolled adult patients who were predominantly female (86%) and Caucasian
(96%) with a mean age of 41 (range, 18 to 65). One study enrolled
adolescents with a mean age of 14 (range, 12 to 17). In the adolescent
study, 54% of the patients were female and 89% were Caucasian. In
all studies, patients were instructed to treat at least 1 moderate
to severe headache. Headache response, defined as a reduction in headache
severity from moderate or severe pain to mild or no pain, was assessed
up to 4 hours after dosing. Associated symptoms such as nausea,
vomiting, photophobia, and phonophobia were also assessed. Maintenance
of response was assessed for up to 24 hours postdose. A second
dose of naratriptan tablets or other medication was allowed 4 to 24 hours
after the initial treatment for recurrent headache. The frequency
and time to use of these additional treatments were also determined.

In all 3 trials in adults utilizing the recommended
dosage regimen and outpatient use, the percentage of patients achieving
headache response 4 hours after treatment, the primary outcome
measure, was significantly greater among patients receiving naratriptan hydrochloride
compared to those who received placebo. In all studies, response to
2.5 mg was numerically greater than response to 1 mg and
in the largest of the 3 studies, there was a statistically significant
greater percentage of patients with headache response at 4 hours
in the 2.5 mg group compared to the 1 mg group. The results are summarized
in Table 1.

In
the single study in adolescents, there were no statistically significant
differences between any of the treatment groups. The headache response
rates at 4 hours (n) were 65% (n = 74), 67% (n = 78),
and 64% (n = 70) for placebo, 1 mg, and 2.5 mg groups, respectively.

Comparisons of drug performance
based upon results obtained in different clinical trials are never
reliable. Because studies are conducted at different times, with different
samples of patients, by different investigators, employing different
criteria and/or different interpretations of the same criteria, under
different conditions (dose, dosing regimen, etc.), quantitative estimates
of treatment response and the timing of response may be expected to
vary considerably from study to study.

The estimated probability of achieving an initial headache response
in adults over the 4 hours following treatment is depicted in
Figure 1.

*The figure shows the
probability over time of obtaining headache response (no or mild pain)
following treatment with naratriptan tablets. The averages displayed are
based on pooled data from the 3 controlled clinical trials providing
evidence of efficacy (Studies 1, 2, and 3). In this Kaplan-Meier plot,
patients not achieving response within 240 minutes were censored
at 240 minutes.

For patients with migraine-associated
nausea, photophobia, and phonophobia at baseline, there was a lower
incidence of these symptoms 4 hours following administration
of 1 mg and 2.5 mg naratriptan tablets compared to placebo.

Four to 24 hours following the initial dose of study treatment,
patients were allowed to use additional treatment for pain relief
in the form of a second dose of study treatment or other medication.
The estimated probability of patients taking a second dose or other
medication for migraine over the 24 hours following the initial
dose of study treatment is summarized in Figure 2.

Figure 2. Estimated Probability
of Patients Taking a Second Dose of Naratriptan Tablets or Other Medication
for Migraine Over the 24 Hours Following the Initial Dose of Study
Treatment*

*Kaplan-Meier plot based on data
obtained in the 3 controlled clinical trials (Studies 1, 2, and 3)
providing evidence of efficacy with patients not using additional
treatments censored at 24 hours. The plot also includes patients
who had no response to the initial dose. Remedication was discouraged
prior to 4 hours postdose.

There is
no evidence that doses of 5 mg provide a greater effect than
2.5 mg. There was no evidence to suggest that treatment with
naratriptan hydrochloride was associated with an increase in the severity or frequency
of migraine attacks. The efficacy of naratriptan tablets was unaffected
by presence of aura; gender, age, or weight of the patient; oral contraceptive
use; or concomitant use of common migraine prophylactic drugs (e.g.,
beta-blockers, calcium channel blockers, tricyclic antidepressants).
There was insufficient data to assess the impact of race on efficacy.

INDICATIONS AND USAGE

Naratriptan tablets
are indicated for the acute treatment of migraine attacks with or
without aura in adults.

Naratriptan tablets are
not intended for the prophylactic therapy of migraine or for use in
the management of hemiplegic or basilar migraine (see CONTRAINDICATIONS).
Safety and effectiveness of naratriptan tablets have not been established
for cluster headache, which is present in an older, predominantly
male population.

CONTRAINDICATIONS

Naratriptan tablets should
not be given to patients with history, symptoms, or signs of ischemic
cardiac, cerebrovascular, or peripheral vascular syndromes. In addition,
patients with other significant underlying cardiovascular diseases
should not receive naratriptan tablets. Ischemic cardiac syndromes include,
but are not limited to, angina pectoris of any type (e.g., stable
angina of effort and vasospastic forms of angina such as the Prinzmetal
variant), all forms of myocardial infarction, and silent myocardial
ischemia. Cerebrovascular syndromes include, but are not limited to,
strokes of any type as well as transient ischemic attacks. Peripheral
vascular disease includes, but is not limited to, ischemic bowel disease
(see WARNINGS).

Because naratriptan tablets may increase blood pressure, they should
not be given to patients with uncontrolled hypertension (see WARNINGS).

WARNINGS

Because of the potential
of this class of compounds (5-HT1B/1D agonists) to
cause coronary vasospasm, naratriptan should not be given to patients
with documented ischemic or vasospastic coronary artery disease (CAD)
(see CONTRAINDICATIONS). It is strongly recommended that 5-HT1 agonists (including naratriptan) not be given to
patients in whom unrecognized CAD is predicted by the presence of
risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity,
diabetes, strong family history of CAD, female with surgical or physiological
menopause, or male over 40 years of age) unless a cardiovascular
evaluation provides satisfactory clinical evidence that the patient
is reasonably free of coronary artery and ischemic myocardial disease
or other significant underlying cardiovascular disease. The sensitivity
of cardiac diagnostic procedures to detect cardiovascular disease
or predisposition to coronary artery vasospasm is modest, at best.
If, during the cardiovascular evaluation, the patient’s medical
history, electrocardiographic, or other investigations reveal findings
indicative of, or consistent with, coronary artery vasospasm or myocardial
ischemia, naratriptan should not be administered (see CONTRAINDICATIONS).

For patients
with risk factors predictive of CAD, who are determined to have a
satisfactory cardiovascular evaluation, it is strongly recommended
that administration of the first dose of naratriptan take place in
the setting of a physician’s office or similar medically staffed
and equipped facility. Because cardiac ischemia can occur in the absence
of clinical symptoms, consideration should be given to obtaining on
the first occasion of use an electrocardiogram (ECG) during the interval
immediately following administration of naratriptan tablets, in these patients
with risk factors.

It is recommended that patients who are intermittent
long-term users of 5-HT1 agonists, including naratriptan tablets,
and who have or acquire risk factors predictive of CAD, as described
above, undergo periodic cardiovascular evaluation as they continue
to use naratriptan tablets.

The systematic approach described above is intended
to reduce the likelihood that patients with unrecognized cardiovascular
disease will be inadvertently exposed to naratriptan.

Cardiac Events and Fatalities Associated With 5-HT1 Agonists

Naratriptan can cause coronary artery vasospasm
(see CLINICAL PHARMACOLOGY). Serious adverse cardiac events, including
acute myocardial infarction, life threatening disturbances of cardiac
rhythm, and death have been reported within a few hours following
the administration of 5-HT1 agonists. Considering the extent
of use of 5-HT1 agonists in patients with migraine, the
incidence of these events is extremely low.

Premarketing Experience With Naratriptan Tablets

Among approximately 3,500 patients with migraine
who participated in premarketing clinical trials of naratriptan tablets,
4 patients treated with single oral doses of naratriptan ranging from
1 to 10 mg experienced asymptomatic ischemic ECG changes with at least
1, who took 7.5 mg, likely due to coronary vasospasm.

Cerebrovascular Events and Fatalities With 5-HT1 Agonists

Cerebral hemorrhage, subarachnoid hemorrhage, stroke,
and other cerebrovascular events have been reported in patients treated
with 5-HT1 agonists, and some have resulted in fatalities.
In a number of cases, it appears possible that the cerebrovascular
events were primary, the agonist having been administered in the incorrect
belief that the symptoms experienced were a consequence of migraine,
when they were not. It should be noted that patients with migraine
may be at increased risk of certain cerebrovascular events (e.g.,
stroke, hemorrhage, transient ischemic attack).

Other Vasospasm-Related Events

5-HT1 agonists may cause vasospastic
reactions other than coronary artery spasm. Both peripheral vascular
ischemia and colonic ischemia with abdominal pain and bloody diarrhea
have been reported with naratriptan.

Increase in Blood Pressure

In healthy volunteers, dose-related increases in
systemic blood pressure have been observed after administration of
up to 20 mg of oral naratriptan. At the recommended doses, the
elevations are generally small, although an increase of systolic pressure
of 32 mmHg was seen in 1 patient following a single 2.5 mg
dose. The effect may be more pronounced in the elderly and hypertensive
patients. A patient who was mildly hypertensive (the baseline blood
pressure was 150/98) experienced a significant increase in blood pressure
to 204/144 mmHg 225 minutes after administration of a 10 mg
oral dose. Significant elevation in blood pressure, including hypertensive
crisis, has been reported on rare occasions in patients receiving
5-HT1 agonists with and without a history of hypertension.
Naratriptan is contraindicated in patients with uncontrolled hypertension
(see CONTRAINDICATIONS).

An 18% increase
in mean pulmonary artery pressure and an 8% increase in mean aortic
pressure was seen following dosing with 1.5 mg of subcutaneous
naratriptan in a study evaluating 10 subjects with suspected CAD undergoing
cardiac catheterization.

Hypersensitivity

Hypersensitivity (anaphylaxis/anaphylactoid) reactions
may occur in patients receiving naratriptan. Such reactions can be
life threatening or fatal. In general, hypersensitivity reactions
to drugs are more likely to occur in individuals with a history of
sensitivity to multiple allergens (see CONTRAINDICATIONS).

PRECAUTIONS

General

Chest discomfort (including pain, pressure, heaviness,
tightness) has been reported after administration of 5-HT1 agonists, including naratriptan tablets. These events have not been associated
with arrhythmias or ischemic ECG changes in clinical trials with naratriptan
tablets. Because naratriptan may cause coronary artery vasospasm,
patients who experience signs or symptoms suggestive of angina following
naratriptan should be evaluated for the presence of CAD or a predisposition
to Prinzmetal variant angina before receiving additional doses of
naratriptan, and should be monitored electrocardiographically if dosing
is resumed and similar symptoms recur. Similarly, patients who experience
other symptoms or signs suggestive of decreased arterial flow, such
as ischemic bowel syndrome or Raynaud syndrome following naratriptan
administration should be evaluated for atherosclerosis or predisposition
to vasospasm (see CONTRAINDICATIONS and WARNINGS).

Naratriptan tablets should also be administered with caution to patients
with diseases that may alter the absorption, metabolism, or excretion
of drugs, such as impaired renal or hepatic function (see CLINICAL
PHARMACOLOGY, CONTRAINDICATIONS, and DOSAGE AND ADMINISTRATION).

Care should be taken to exclude other potentially
serious neurological conditions before treating headache in patients
not previously diagnosed with migraine or who experience a headache
that is atypical for them. There have been rare reports where patients
received 5-HT1 agonists for severe headaches that were
subsequently shown to have been secondary to an evolving neurologic
lesion (see WARNINGS).

For a given attack,
if a patient has no response to the first dose of naratriptan hydrochloride, the diagnosis
of migraine should be reconsidered before administration of a second
dose.

Binding to Melanin-Containing Tissues

In rats treated with a single oral dose (10 mg/kg)
of radiolabeled naratriptan, the elimination half-life of radioactivity
from the eye was 90 days, suggesting that naratriptan and/or
its metabolites may bind to the melanin of the eye. Because there
could be accumulation in melanin-rich tissues over time, this raises
the possibility that naratriptan could cause toxicity in these tissues
after extended use. Although no systematic monitoring of ophthalmologic
function was undertaken in clinical trials, and no specific recommendations
for ophthalmologic monitoring are offered, prescribers should be aware
of the possibility of long-term ophthalmologic effects.

Changes in the Precorneal Tear Film

Dogs receiving oral naratriptan showed transient
changes in the precorneal tear film. Corneal stippling was seen at
the lowest dose tested, 1 mg/kg/day, and occurred intermittently
from day 1 throughout the first 2 to 3 weeks of treatment.
Although a no-effect dose was not established, the exposure at the
lowest dose tested was approximately 5 times the human exposure after
a 5 mg oral dose.

Information for Patients

See PATIENT INFORMATION at the end of this labeling for the text of the separate leaflet provided for patients.

Patients should be cautioned about
the risk of serotonin syndrome with the use of naratriptan or other
triptans, especially during combined use with SSRIs or SNRIs.

Laboratory Tests

No specific laboratory tests are recommended for
monitoring patients prior to and/or after treatment with naratriptan tablets.

Drug Interactions

Cases of life-threatening serotonin syndrome have
been reported during combined use of SSRIs or SNRIs and triptans (see
WARNINGS).

Ergot-Containing Drugs

Ergot-containing drugs have been reported to cause
prolonged vasospastic reactions. Because there is a theoretical basis
that these effects may be additive, use of ergotamine-containing or
ergot-type medications (like dihydroergotamine or methysergide) and
naratriptan within 24 hours is contraindicated (see CONTRAINDICATIONS).

Other 5-HT1 Agonists

The administration of naratriptan with other 5-HT1 agonists has not been evaluated in migraine patients. Because
their vasospastic effects may be additive, coadministration of naratriptan
and other 5-HT1 agonists within 24 hours of each other
is not recommended (see CONTRAINDICATIONS).

Drug/Laboratory Test Interactions

Naratriptan tablets
are not known to interfere with commonly employed clinical laboratory
tests.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Lifetime carcinogenicity
studies, 104 weeks in duration, were carried out in mice and
rats by oral gavage. There was no evidence of an increase in tumors
related to naratriptan administration in mice receiving up to 200 mg/kg/day.
That dose was associated with a plasma area-under-the-curve (AUC)
exposure that was 110 times the exposure in humans receiving the maximum
recommended daily dose of 5 mg. Two rat studies were conducted,
1 using a standard diet and the other a nitrite-supplemented diet
(naratriptan can be nitrosated in vitro to form a mutagenic product
that has been detected in the stomachs of rats fed a high nitrite
diet). Doses of 5, 20, and 90 mg/kg were associated with week
13 AUC exposures that in the standard diet study were 7, 40, and 236
times, respectively, and in the nitrite-supplemented diet study were
7, 29, and 180 times, respectively, the exposure attained in humans
given the maximum recommended daily dose of 5 mg. In both studies,
there was an increase in the incidence of thyroid follicular hyperplasia
in high-dose males and females and in thyroid follicular adenomas
in high-dose males. In the standard diet study only, there was also
an increase in the incidence of benign c-cell adenomas in the thyroid
of high-dose males and females. The exposures achieved at the no-effect
dose for thyroid tumors were 40 (standard diet) and 29 (nitrite-supplemented
diet) times the exposure achieved in humans receiving the maximum
recommended daily dose of 5 mg. In the nitrite-supplemented diet
study only, the incidence of benign lymphocytic thymoma was increased
in all treated groups of females. It was not determined if the nitrosated
product is systemically absorbed. However, no changes were seen in
the stomachs of rats in that study.

Mutagenesis

Naratriptan was not mutagenic when tested in 2 gene
mutation assays, the Ames test and the in vitro thymidine locus mouse
lymphoma assay. It was not clastogenic in 2 cytogenetics assays, the
in vitro human lymphocyte assay and the in vivo mouse micronucleus
assay. Naratriptan can be nitrosated in vitro to form a mutagenic
product (WHO nitrosation assay) that has been detected in the stomachs
of rats fed a nitrite-supplemented diet.

Impairment of Fertility

In a reproductive toxicity study in which male and
female rats were dosed prior to and throughout the mating period with
10, 60, 170, or 340 mg/kg/day (plasma exposures [AUC] approximately
11, 70, 230, and 470 times, respectively, the human exposure at the
maximum recommended daily dose [MRDD] of 5 mg), there was a treatment-related
decrease in the number of females exhibiting normal estrous cycles
at doses of 170 mg/kg/day or greater and an increase in preimplantation
loss at 60 mg/kg/day or greater. In high-dose group males, testicular/epididymal
atrophy accompanied by spermatozoa depletion reduced mating success
and may have contributed to the observed preimplantation loss. The
exposures achieved at the no-effect doses for preimplantation loss,
anestrus, and testicular effects were approximately 11, 70, and 230
times, respectively, the exposures in humans receiving the MRDD.

In a study in which rats were dosed orally with 10,
60, or 340 mg/kg/day for 6 months, changes in the female
reproductive tract including atrophic or cystic ovaries and anestrus
were seen at the high dose. The exposure at the no-effect dose of
60 mg/kg was approximately 85 times the exposure in humans
receiving the MRDD.

Pregnancy

Teratogenic Effects:

Pregnancy Category
C. There are no adequate and well-controlled studies in pregnant women;
therefore, naratriptan should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.

When pregnant rats were administered naratriptan during
the period of organogenesis at doses of 10, 60, or 340 mg/kg/day,
there was a dose-related increase in embryonic death, with a statistically
significant difference at the highest dose, and incidences of fetal
structural variations (incomplete/irregular ossification of skull
bones, sternebrae, ribs) were increased at all doses. The maternal
plasma exposures (AUC) at these doses were approximately 11, 70, and
470 times the exposure in humans at the MRDD. The high dose was
maternally toxic, as evidenced by decreased maternal body weight gain
during gestation. A no-effect dose for developmental toxicity in rats
exposed during organogenesis was not established.

When doses of 1, 5, or 30 mg/kg/day were given to pregnant
Dutch rabbits throughout organogenesis, the incidence of a specific
fetal skeletal malformation (fused sternebrae) was increased at the
high dose, and increased incidences of embryonic death and fetal variations
(major blood vessel variations, supernumerary ribs, incomplete skeletal
ossification) were observed at all doses (4, 20, and 120 times,
respectively, the MRDD on a body surface area basis). Maternal toxicity
(decreased body weight gain) was evident at the high dose in this
study. In a similar study in New Zealand White rabbits (1, 5, or 30 mg/kg/day
throughout organogenesis), decreased fetal weights and increased incidences
of fetal skeletal variations were observed at all doses (maternal
exposures equivalent to 2.5, 19, and 140 times exposure in humans
receiving the MRDD), while maternal body weight gain was reduced at
5 mg/kg or greater. A no-effect dose for developmental toxicity
in rabbits exposed during organogenesis was not established.

When female rats were treated with 10, 60, or 340 mg/kg/day
during late gestation and lactation, offspring behavioral impairment
(tremors) and decreased offspring viability and growth were observed
at doses of 60 mg/kg or greater, while maternal toxicity occurred
only at the highest dose. Maternal exposures at the no-effect dose
for developmental effects in this study were approximately 11 times
the exposure in humans receiving the MRDD.

Nursing Mothers

Naratriptan-related material is excreted in the
milk of rats. Therefore, caution should be exercised when considering
the administration of naratriptan tablets to a nursing woman.

Pediatric Use

Safety and effectiveness of naratriptan tablets in pediatric
patients (younger than 18 years) have not been established.

One randomized, placebo-controlled clinical trial
evaluating oral naratriptan (0.25 to 2.5 mg) in pediatric patients
aged 12 to 17 years evaluated a total of 300 adolescent migraineurs.
This study did not establish the efficacy of oral naratriptan compared
to placebo in the treatment of migraine in adolescents (see CLINICAL
TRIALS). Adverse events observed in this clinical trial were similar
in nature to those reported in clinical trials in adults.

Geriatric Use

The use of naratriptan tablets in elderly patients is
not recommended.

Naratriptan is known to
be substantially excreted by the kidney, and the risk of adverse reactions
to this drug may be greater in elderly patients who have reduced renal
function. In addition, elderly patients are more likely to have decreased
hepatic function; they are at higher risk for CAD; and blood pressure
increases may be more pronounced in the elderly. Clinical studies
of naratriptan tablets did not include patients over 65 years of age.

ADVERSE REACTIONS

Serious cardiac events,
including some that have been fatal, have occurred following the use
of 5-HT1 agonists. These events are extremely rare and most
have been reported in patients with risk factors predictive of CAD.
Events reported have included coronary artery vasospasm, transient
myocardial ischemia, myocardial infarction, ventricular tachycardia,
and ventricular fibrillation (see CONTRAINDICATIONS, WARNINGS, and
PRECAUTIONS).

Incidence in Controlled Clinical Trials

The most common adverse events were paresthesias,
dizziness, drowsiness, malaise/fatigue, and throat/neck symptoms,
which occurred at a rate of 2% and at least 2 times placebo rate.
Since patients treated only 1 to 3 headaches in the controlled clinical
trials, the opportunity for discontinuation of therapy in response
to an adverse event was limited. In a long-term, open-label study
where patients were allowed to treat multiple migraine attacks for
up to 1 year, 15 patients (3.6%) discontinued treatment due to
adverse events.

Table 2 lists adverse
events that occurred in 5 placebo-controlled clinical trials of approximately
1,752 exposures to placebo and naratriptan tablets in adult migraine patients.
The events cited reflect experience gained under closely monitored
conditions of clinical trials in a highly selected patient population.
In actual clinical practice or in other clinical trials, these frequency
estimates may not apply, as the conditions of use, reporting behavior,
and the kinds of patients treated may differ. Only events that occurred
at a frequency of 2% or more in the group treated with naratriptan tablets
2.5 mg and were more frequent in that group than in the placebo
group are included in Table 2. From this table, it appears that
many of these adverse events are dose related.

One event (vomiting)
present in more than 1% of patients receiving naratriptan tablets occurred
more frequently on placebo than on naratriptan 2.5 mg.

Naratriptan tablets are generally well tolerated. Most
adverse reactions were mild and transient.

The incidence of adverse events in placebo-controlled clinical
trials was not affected by age or weight of the patients, duration
of headache prior to treatment, presence of aura, use of prophylactic
medications, or tobacco use. There was insufficient data to assess
the impact of race on the incidence of adverse events.

Other Events Observed in Association With the Administration
of Naratriptan Tablets

In the paragraphs that follow, the frequencies of
less commonly reported adverse clinical events are presented. Because
the reports include events observed in open and uncontrolled studies,
the role of naratriptan tablets in their causation cannot be reliably determined.
Furthermore, variability associated with adverse event reporting,
the terminology used to describe adverse events, etc., limit the value
of the quantitative frequency estimates provided. Event frequencies
are calculated as the number of patients reporting an event divided
by the total number of patients (n = 3,557) exposed to oral
naratriptan doses up to 10 mg. All reported events are included
except those already listed in the previous table, those too general
to be informative, and those not reasonably associated with the use
of the drug. Events are further classified within body system categories
and enumerated in order of decreasing frequency using the following
definitions: frequent adverse events are those occurring in at least
1/100 patients, infrequent adverse events are those occurring in 1/100
to 1/1,000 patients, and rare adverse events are those occurring in
fewer than 1/1,000 patients.

Urology

Observed During Clinical Practice

The following section enumerates potentially important
adverse events that have occurred in clinical practice and that have
been reported spontaneously to various surveillance systems. The events
enumerated represent reports arising from both domestic and nondomestic
use of naratriptan. These events do not include those already listed
in the ADVERSE REACTIONS section above. Because the reports cite events
reported spontaneously from worldwide postmarketing experience, frequency
of events and the role of naratriptan in their causation cannot be
reliably determined.

Neurologic

DRUG ABUSE AND DEPENDENCE

In one clinical study enrolling 12 subjects,
all of whom had experience using oral opiates and other psychoactive
drugs, naratriptan tablets produced less intense subjective responses ordinarily
associated with many drugs of abuse than did codeine (30 to 90 mg).

OVERDOSAGE

A patient who was mildly hypertensive experienced
a significant increase in blood pressure after administration of a
10 mg dose starting at 30 minutes (baseline value of 150/98 to
204/144 mmHg 225 minutes). This event resolved after treatment
with antihypertensive therapy. Oral administration of 25 mg of
naratriptan in 1 healthy young male subject increased blood pressure
from 120/67 mmHg pretreatment up to 191/113 mmHg at approximately
6 hours postdose and resulted in adverse events including lightheadedness,
tension in the neck, tiredness, and loss of coordination. Blood pressure
returned to near baseline by 8 hours after dosing without any
pharmacological intervention.

The elimination half-life of naratriptan
is about 6 hours (see CLINICAL PHARMACOLOGY), and therefore monitoring
of patients after overdose with naratriptan tablets should continue for
at least 24 hours or while symptoms or signs persist. There is
no specific antidote to naratriptan. Standard supportive treatment
should be applied as required. If the patient presents with chest
pain or other symptoms consistent with angina pectoris, ECG monitoring
should be performed for evidence of ischemia. It is unknown what effect
hemodialysis or peritoneal dialysis has on the serum concentrations
of naratriptan.

DOSAGE AND ADMINISTRATION

In controlled clinical trials, single doses of
1 mg and 2.5 mg of naratriptan tablets taken with fluid were effective
for the acute treatment of migraines in adults. A greater proportion
of patients had headache response following a 2.5 mg dose than following
a 1 mg dose (see CLINICAL TRIALS). Individuals may vary in response
to doses of naratriptan tablets. The choice of dose should therefore be
made on an individual basis, weighing the possible benefit of the
2.5 mg dose with the potential for a greater risk of adverse events.
If the headache returns or if the patient has only partial response,
the dose may be repeated once after 4 hours, for a maximum dose
of 5 mg in a 24-hour period. There is evidence that doses of
5 mg do not provide a greater effect than 2.5 mg.

The safety of treating, on average, more than 4 headaches in a 30-day period has not been established.

Renal Impairment

The use of naratriptan hydrochloride is contraindicated in patients
with severe renal impairment (creatinine clearance, <15 mL/min)
because of decreased clearance of the drug (see CONTRAINDICATIONS
and CLINICAL PHARMACOLOGY). In patients with mild to moderate renal
impairment, the maximum daily dose should not exceed 2.5 mg over
a 24-hour period and a lower starting dose should be considered.

Hepatic Impairment

The use of naratriptan hydrochloride is contraindicated in patients
with severe hepatic impairment (Child-Pugh grade C) because of decreased
clearance (see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY). In patients
with mild or moderate hepatic impairment, the maximum daily dose should
not exceed 2.5 mg over a 24-hour period and a lower starting
dose should be considered (see CLINICAL PHARMACOLOGY).

HOW SUPPLIED

Naratriptan tablets USP
2.5 mg of naratriptan (base) as the hydrochloride. Naratriptan tablets USP, 2.5 mg, are green, round shaped, biconvex, film-coated tablets debossed with “437” on one side and plain on other side.

PATIENT INFORMATION

The following wording is contained in a separate leaflet provided for patients.

Information for the Patient

Naratriptan Tablets USP

Please read this leaflet carefully before you take naratriptan tablets. This leaflet provides a summary of the information available about your medicine. Please do not throw away this leaflet until you have finished your medicine. You may need to read this leaflet again. This leaflet does not contain all the information on naratriptan tablets. For further information or advice, ask your doctor or pharmacist.

Information About Your Medicine:

The name of your medicine is naratriptan tablets. They can be obtained only by prescription from your doctor. The decision to use naratriptan tablets is one that you and your doctor should make jointly, taking into account your individual preferences and medical circumstances. If you have risk factors for heart disease (such as high blood pressure, high cholesterol, obesity, diabetes, smoking, strong family history of heart disease, or you are postmenopausal or a male over 40), you should tell your doctor, who should evaluate you for heart disease in order to determine if naratriptan tablets are appropriate for you. The majority of those who have taken naratriptan tablets have not experienced any significant side effects. Rarely, deaths and/or serious heart problems have been reported with this class of medicines; in all but a few instances, however, these deaths and/or serious heart problems occurred in people with heart disease and it was not clear whether these medicines were a contributing factor.

The Purpose of Your Medicine:

Naratriptan tablets are intended to relieve your migraine, but not to prevent or reduce the number of attacks you experience. Use naratriptan tablets only to treat an actual migraine attack.

Important Questions to Consider Before Taking Naratriptan Tablets:

If the answer to any of the following questions is YES or if you do not know the answer, then please discuss it with your doctor before you use naratriptan tablets.

Are you pregnant? Do you think you might be pregnant? Are you trying to become pregnant? Are you not using adequate contraception? Are you breastfeeding?

Do you have any chest pain, heart disease, shortness of breath, or irregular heartbeats? Have you had a heart attack?

Do you have risk factors for heart disease (such as high blood pressure, high cholesterol, obesity, diabetes, smoking, strong family history of heart disease, or you are postmenopausal or a male over 40)?

Have you had a stroke, transient ischemic attacks (TIAs), or Raynaud syndrome?

Do you have high blood pressure?

Have you ever had to stop taking this or any other medicine because of an allergy or other problems?

Are you taking any other migraine medicines, including other 5-HT1 agonists such as IMITREX®* (sumatriptan/sumatriptan succinate), or medicines containing ergotamine, dihydroergotamine, or methysergide?

Are you taking any medicine for depression or other disorders such as selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs)? Common SSRIs are citalopram HBr (CELEXA®*), escitalopram oxalate (LEXAPRO®*), paroxetine (PAXIL®*), fluoxetine (PROZAC®*/SARAFEM®*), olanzapine/fluoxetine (SYMBYAX®*), sertraline (ZOLOFT®*), and fluvoxamine. Common SNRIs are duloxetine (CYMBALTA®*) and venlafaxine (EFFEXOR®*).

Have you had, or do you have, any disease of the kidney or liver?

Is this headache different from your usual migraine attacks?

Remember, if you answered YES to any of the above questions, then discuss it with your doctor.

The Use of Naratriptan Tablets During Pregnancy:

Do not use naratriptan tablets if you are pregnant, think you might be pregnant, are trying to become pregnant, or are not using adequate contraception, unless you have discussed this with your doctor.

How to Use Naratriptan Tablets:

For adults, the usual dose is a single tablet taken whole with fluids. It may be given at any time after the headache starts. For an individual attack, if you have no response to the first tablet, do not take a second tablet without first talking to your doctor. If you need more relief due to a partial response or return of your headache after the first tablet, a second tablet may be taken, but not sooner than 4 hours following the first tablet. Do not take more than a total of 2 naratriptan tablets in any 24 hour period. If you have kidney or liver disease, take as directed by your doctor.

Side Effects to Watch for:

Some patients experience pain or tightness in the chest or throat when using naratriptan tablets. If this happens to you, then discuss it with your doctor before using any more naratriptan tablets. If the chest pain, tightness, or pressure is severe or does not go away, call your doctor immediately.

Some people may have a reaction called serotonin syndrome when they use certain types of antidepressants, SSRIs or SNRIs, while taking naratriptan tablets. Symptoms may include confusion, hallucinations, fast heart beat, feeling faint, fever, sweating, muscle spasm, difficulty walking, and/or diarrhea. Call your doctor immediately if you have any of these symptoms after taking naratriptan tablets.

Shortness of breath; wheeziness; heart throbbing, swelling of eyelids, face, or lips; or a skin rash, skin lumps, or hives happens rarely. If it happens to you, then tell your doctor immediately. Do not take any more naratriptan tablets unless your doctor tells you to do so.

Some people may have feelings of tingling, heat, flushing (redness of face lasting a short time), heaviness or pressure after treatment with naratriptan tablets. A few people may feel drowsy, dizzy, tired, or sick. Tell your doctor of these symptoms at your next visit.

If you feel unwell in any other way or have any symptoms that you do not understand, you should contact your doctor immediately.

What to Do if an Overdose Is Taken:

If you have taken more medicine than you have been told, contact either your doctor, hospital emergency department, or nearest poison control center immediately.

Storing Your Medicine:

Keep your medicine in a safe place where children cannot reach it. It may be harmful to children. Store your medicine away from heat and light. Do not store at temperatures above 77°F (25°C). If your medicine has expired (the expiration date is printed on the treatment pack), throw it away as instructed. If your doctor decides to stop your treatment, do not keep any leftover medicine unless your doctor tells you to. Throw away your medicine as instructed.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.